The British patent Number of 2 078 719 A describes very effective fungicide compounds, which have substantial plant growth regulating effect as well. The above compounds are illustrated by formula (A)
wherein the meaning of R is alkyl, cycloalkyl, aryl or aralkyl group, or the derivatives of these containing one or two halogen atoms or alkoxy, phenyl, phenoxy or trifluoromethyl substituted aryl and benzyl groups and Y1 and Y2 independently are —N═ or —CH═ group.
According to the British Patent Number of 2 099 818 A the compound 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazole-1-yl)-propane-2-ol belonging to the above group (further on fluconazole) can be used as human fungicide too. Fluconazole is among others the active ingredient of Diflucan, which is a very effective human fungicide drug on the market.
According to the British Patent Number of 2 078 719 A propane-2-ol derivatives of formula (A) are synthesized by reacting a Grignard compound of formula R—Mg-Halogen—wherein the meaning of R is as defined above—with dichloroacetone. The so formed 1,3-dichloropropane-2-ol derivative of formula (VI)
is reacted with excess imidazole or triazole salt, for example sodium salt in protic or aprotic media (for example in dimethylformamide). The reaction can be carried out with epoxy derivatives as well, which are in situ formed from the dihalogen compound in the presence of a base by elimination of hydrogen chloride. The desired compounds can also be synthesized by reacting the appropriate 1,3-bisimidazolyl, or 1,3-bis(1,2,4-triazole-1-yl)-acetone with a Grignard compound of formula R—Mg-Halogen. According to an other synthetic pathway compounds of formula (VII)—wherein the meaning of R and Y1 is as defined above
are converted into compounds of formula (IV), containing an R substituent instead of R1, with dimethyl oxosulfonium methylide,
and these are reacted with imidazole or triazole sodium salt similarly to the above-mentioned process. The starting materials are prepared according to known procedures.
The process for the synthesis of the active substance of fluconazole described in the British Patent Number of 2 099 818 A uses the compounds of formula (VI) and (IV), which contain R substituent instead of R1, as starting materials, but a base and triazole are used as reagents instead of sodium triazolate.
The common feature of procedures of both patents is that the isolation of reaction products is carried out by extraction after dilution of the reaction mixture with water, followed by purification with column chromatography or vacuum distillation or other methods. The yield of the obtained product is 30–50%.
According to the Spanish Patent Number ES 549 020 A1 1 mole of 1,3-dichloroacetone is reacted with 2 mole of 1,2,4-triazole, then the 1,3-bis(1,2,4-triazole-1-yl)-propan-2-on obtained with low yield is reacted with 2,4-difluorophenylmagnesium bromide to give fluconazole. The yield is about 45% calculated on the Grignard reagent.
The common feature of the procedures described in the Spanish Patents Number of ES 549 021 A1, ES 549 022 A1 and ES 549 684 A1 is, that one or both triazolyl groups of fluconazole are introduced into the molecule with (1,2,4-triazole-1-yl)-methylmagnesium halogenide. According to the descriptions the yields are about 45–55%. The Grignard reagents containing triazolyl groups are known to be unstable, or sometimes inactive, therefor they react with low yield. During the reproduction of the procedures described in these patents the yield was always below 10%.
The Spanish Patent Number of ES 2 026 416 describes a better procedure, than the above mentioned ones. According to this 1-(1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-halogen-propan-2-ol is reacted with 4-amino-1,2,4-triazole, and the obtained 1-(1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-(4-amino-1,2,4-triazole-1-yl)-propan-2-ol is diazotized and the so formed diazonium salt is hydrolyzed to remove the amino group. The given yields are 78% for the first step and 85% for the second step. This process has several disadvantages from industrial point of view. The first one is, that the 3-halogen-propan-2-ol derivative used as starting material is synthesized from an epoxy derivative of formula (IV) by refluxing in a corrosive hydrogen halogenide medium. Further disadvantage is, that 4-amino-1,2,4-triazole used as reagent can only be bought as fine chemicals. The diazotation reaction and the hydrolysis of the diazonium salt on industrial scale are very dangerous procedures. Finally the combined yield of the multistep process is only 42–43%.
In the December issue of 1995 of the Journal of Ph. Sciences (Vol. 84, No. 12.) the crystal forms I and II of fluconazole, as well as the X-ray powder diffraction and Raman spectra of different crystal modifications are described without the process of their synthesis.
The Patent Number of GB 2270521 describes the synthesis of fluconazole monohydrate from anhydrous fluconazole. According to the X-ray powder diffraction data the anhydrous fluconazole, used as starting material, is identical with the crystal modification II. In this description the Patent Number of U.S. Pat. No. 4,404,219 is referred to for the synthesis of this crystal modification, but in that there is no reference for the crystal modification of the product.